Electronic Thesis and Dissertation Repository

Degree

Master of Science

Program

Physiology

Supervisor

Dr. Nica Borradaile

Abstract

Nicotinic acid (NA) can improve vascular function and regeneration independent of correcting dyslipidemia. NA, as a potential biosynthetic precursor for NAD+, may elicit these vascular benefits through SIRT-mediated NAD+-dependent responses. We hypothesized that NA improves endothelial cell function under lipotoxic conditions through NAD+-dependent pathways. Angiogenic function in excess palmitate was assessed by tube formation assay following treatment of human microvascular endothelial cells (HMVEC) with NA or nicotinamide mononucleotide (NMN; a direct NAD+ precursor). Both NA and NMN improved HMVEC angiogenic function during palmitate overload. Only NMN increased cellular NAD+ and SIRT1 activity, while both compounds activated SIRT2/3. By microarray, NA did not induce expression of known SIRT-regulated genes. However, we found that HMVEC robustly express NA receptor GRP109A, whose specific activation recapitulated NA-induced improvements in angiogenic function. We conclude that NA improves in vitro HMVEC angiogenic function under lipotoxic conditions, perhaps through GPR109A, but likely unrelated to NAD+ biosynthesis and SIRT activation.


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